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PDBsum entry 2c17
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Oxidoreductase PDB id
2c17

 

 

 

 

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Contents
Protein chain
454 a.a.
Ligands
HEM
Theoretical model
PDB id:
2c17
Name: Oxidoreductase
Title: Computational model of human p450c17
Structure: Cytochrome p450 xviia1. Chain: a. Synonym: p450-c17, steroid 17-alpha-hydroxylase, 17/20- lyase. Ec: 1.14.99.9
Source: Homo sapiens. Human
Authors: R.J.Auchus,W.L.Miller
Key ref: R.J.Auchus and W.L.Miller (1999). Molecular modeling of human P450c17 (17alpha-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations. Mol Endocrinol, 13, 1169-1182. PubMed id: 10406467
Date:
02-Jun-99     Release date:   19-Jul-99    
PROCHECK
Go to PROCHECK summary
 Headers
 References

Protein chain
Pfam   ArchSchema ?
P05093  (CP17A_HUMAN) -  Steroid 17-alpha-hydroxylase/17,20 lyase
Seq:
Struc: 		508 a.a.
454 a.a.
Key:    PfamA domain  Secondary structure

 

 
Mol Endocrinol 13:1169-1182 (1999)
PubMed id: 10406467  
 
 
Molecular modeling of human P450c17 (17alpha-hydroxylase/17,20-lyase): insights into reaction mechanisms and effects of mutations.
R.J.Auchus, W.L.Miller.
 
  ABSTRACT  
 
P450c17 (17alpha-hydroxylase/17,20-lyase) catalyzes steroid 17alpha-hydroxylase and 17,20-lyase activities in the biosynthesis of androgens and estrogens. These two activities are differentially regulated in a tissue-specific and developmentally programmed manner. To visualize the active site topology of human P450c17 and to study the structural basis of its substrate specificity and catalytic selectivity, we constructed a second-generation computer-graphic model of human P450c17. The energetics of the model are comparable to those of the principal template of the model, P450BMP, as determined from its crystallographic coordinates. The protein structure analysis programs PROCHECK, WHATIF, and SurVol indicate that the predicted P450c17 structure is reasonable. The hydrophobic active site accommodates both delta4 and delta5 steroid substrates in a catalytically favorable orientation. The predicted contributions of positively charged residues to the redox-partner binding site were confirmed by site-directed mutagenesis. Molecular dynamic simulations with pregnenolone, 17-OH-pregnenolone, progesterone, and 17-OH-progesterone docked into the substrate-binding pocket demonstrated that regioselectivity of the hydroxylation reactions is determined both by proximity of hydrogens to the iron-oxo complex and by the stability of the carbon radicals generated after hydrogen abstraction. The model explains the activities of all known naturally occurring and synthetic human P450c17 mutants. The model predicted that mutation of lysine 89 would disrupt 17,20-lyase activity to a greater extent than 17alpha-hydroxylase activity; expression of a test mutant, K89N, in yeast confirmed this prediction. Hydrogen peroxide did not support catalysis of the 17,20-lyase reaction, as would be predicted by mechanisms involving a ferryl peroxide. Our present model and biochemical data suggest that both the hydroxylase and lyase activities proceed from a common steroid-binding geometry by an iron oxene mechanism. This model will facilitate studies of sex steroid synthesis and its disorders and the design of specific inhibitors useful in chemotherapy of sex steroid-dependent cancers.
 

Literature references that cite this PDB file's key reference

  PubMed id Reference
21511288 R.Samtani, M.Bajpai, K.Vashisht, P.K.Ghosh, and K.N.Saraswathy (2011).
Hypospadias Risk and Polymorphism in SRD5A2 and CYP17 Genes: Case-Control Study Among Indian Children.
  J Urol, 185, 2334-2339.  
20939704 A.A.Bremer (2010).
Polycystic ovary syndrome in the pediatric population.
  Metab Syndr Relat Disord, 8, 375-394.  
19267349 J.A.Locke, L.Fazli, H.Adomat, J.Smyl, K.Weins, A.A.Lubik, D.B.Hales, C.C.Nelson, M.E.Gleave, and E.S.Tomlinson Guns (2009).
A novel communication role for CYP17A1 in the progression of castration-resistant prostate cancer.
  Prostate, 69, 928-937.  
18720009 R.J.Auchus (2009).
Non-traditional metabolic pathways of adrenal steroids.
  Rev Endocr Metab Disord, 10, 27-32.  
19805543 S.Praporski, S.M.Ng, A.D.Nguyen, C.J.Corbin, A.Mechler, J.Zheng, A.J.Conley, and L.L.Martin (2009).
Organization of cytochrome P450 enzymes involved in sex steroid synthesis: PROTEIN-PROTEIN INTERACTIONS IN LIPID MEMBRANES.
  J Biol Chem, 284, 33224-33232.  
18821018 W.L.Miller (2009).
Androgen synthesis in adrenarche.
  Rev Endocr Metab Disord, 10, 3.  
18720339 M.A.Pinto-Bazurco Mendieta, M.Negri, Q.Hu, U.E.Hille, C.Jagusch, K.Jahn-Hoffmann, U.Müller-Vieira, D.Schmidt, T.Lauterbach, and R.W.Hartmann (2008).
CYP17 inhibitors. Annulations of additional rings in methylene imidazole substituted biphenyls: synthesis, biological evaluation and molecular modelling.
  Arch Pharm (Weinheim), 341, 597-609.  
18707589 T.A.Pechurskaya, O.P.Lukashevich, A.A.Gilep, and S.A.Usanov (2008).
Engineering, expression, and purification of "soluble" human cytochrome P45017alpha and its functional characterization.
  Biochemistry (Mosc), 73, 806-811.  
16915000 C.E.Flück, and W.L.Miller (2006).
P450 oxidoreductase deficiency: a new form of congenital adrenal hyperplasia.
  Curr Opin Pediatr, 18, 435-441.  
16426683 T.Hakki, and R.Bernhardt (2006).
CYP17- and CYP11B-dependent steroid hydroxylases as drug development targets.
  Pharmacol Ther, 111, 27-52.  
15649098 G.L.Warne, S.Grover, and J.D.Zajac (2005).
Hormonal therapies for individuals with intersex conditions: protocol for use.
  Treat Endocrinol, 4, 19-29.  
16185177 J.S.Markowitz, C.L.DeVane, J.G.Lewis, K.D.Chavin, J.S.Wang, and J.L.Donovan (2005).
Effect of Ginkgo biloba extract on plasma steroid concentrations in healthy volunteers: a pilot study.
  Pharmacotherapy, 25, 1337-1340.  
15793702 N.Huang, A.V.Pandey, V.Agrawal, W.Reardon, P.D.Lapunzina, D.Mowat, E.W.Jabs, G.Van Vliet, J.Sack, C.E.Flück, and W.L.Miller (2005).
Diversity and function of mutations in p450 oxidoreductase in patients with Antley-Bixler syndrome and disordered steroidogenesis.
  Am J Hum Genet, 76, 729-749.  
16467261 W.L.Miller, N.Huang, A.V.Pandey, C.E.Flück, and V.Agrawal (2005).
P450 oxidoreductase deficiency: a new disorder of steroidogenesis.
  Ann N Y Acad Sci, 1061, 100-108.  
14758361 C.E.Flück, T.Tajima, A.V.Pandey, W.Arlt, K.Okuhara, C.F.Verge, E.W.Jabs, B.B.Mendonça, K.Fujieda, and W.L.Miller (2004).
Mutant P450 oxidoreductase causes disordered steroidogenesis with and without Antley-Bixler syndrome.
  Nat Genet, 36, 228-230.  
15519890 R.J.Auchus (2004).
The backdoor pathway to dihydrotestosterone.
  Trends Endocrinol Metab, 15, 432-438.  
15169901 S.R.Bair, and S.H.Mellon (2004).
Deletion of the mouse P450c17 gene causes early embryonic lethality.
  Mol Cell Biol, 24, 5383-5390.  
15350602 W.L.Miller (2004).
P450 oxidoreductase deficiency: a new disorder of steroidogenesis with multiple clinical manifestations.
  Trends Endocrinol Metab, 15, 311-315.  
14661979 S.Izumi, H.Kaneko, T.Yamazaki, T.Hirata, and S.Kominami (2003).
Membrane topology of guinea pig cytochrome P450 17 alpha revealed by a combination of chemical modifications and mass spectrometry.
  Biochemistry, 42, 14663-14669.  
12112031 R.W.Hartmann, P.B.Ehmer, S.Haidar, M.Hector, J.Jose, C.D.Klein, S.B.Seidel, T.F.Sergejew, B.G.Wachall, G.A.Wächter, and Y.Zhuang (2002).
Inhibition of CYP 17, a new strategy for the treatment of prostate cancer.
  Arch Pharm (Weinheim), 335, 119-128.  
11422109 Y.Takeda, T.Yoneda, M.Demura, K.Furukawa, H.Koshida, I.Miyamori, and H.Mabuchi (2001).
Genetic analysis of the cytochrome P-450c17alpha (CYP17) and aldosterone synthase (CYP11B2) in Japanese patients with 17alpha-hydroxylase deficiency.
  Clin Endocrinol (Oxf), 54, 751-758.  
The most recent references are shown first. Citation data come partly from CiteXplore and partly from an automated harvesting procedure. Note that this is likely to be only a partial list as not all journals are covered by either method. However, we are continually building up the citation data so more and more references will be included with time.

 

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